JPH0559119B2 - - Google Patents
Info
- Publication number
- JPH0559119B2 JPH0559119B2 JP2951284A JP2951284A JPH0559119B2 JP H0559119 B2 JPH0559119 B2 JP H0559119B2 JP 2951284 A JP2951284 A JP 2951284A JP 2951284 A JP2951284 A JP 2951284A JP H0559119 B2 JPH0559119 B2 JP H0559119B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- aroylthymidine
- general formula
- derivative according
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 230000000259 anti-tumor effect Effects 0.000 claims description 36
- -1 methoxyphenoxycarbonyl group Chemical group 0.000 claims description 26
- 231100000419 toxicity Toxicity 0.000 claims description 21
- 230000001988 toxicity Effects 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 9
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 claims 1
- 125000004673 propylcarbonyl group Chemical group 0.000 claims 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 150000001875 compounds Chemical class 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 16
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 16
- 229940104230 thymidine Drugs 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 238000000921 elemental analysis Methods 0.000 description 14
- 150000004820 halides Chemical class 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 238000002211 ultraviolet spectrum Methods 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 230000037396 body weight Effects 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- 210000000265 leukocyte Anatomy 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 208000018522 Gastrointestinal disease Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 238000004820 blood count Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 208000010643 digestive system disease Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 208000018685 gastrointestinal system disease Diseases 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 231100001274 therapeutic index Toxicity 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- GPZXFICWCMCQPF-UHFFFAOYSA-N 2-methylbenzoyl chloride Chemical compound CC1=CC=CC=C1C(Cl)=O GPZXFICWCMCQPF-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000006268 Sarcoma 180 Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- RGVBNBFNSBMXID-QJPTWQEYSA-N [(2r,3s,5r)-3-acetyloxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl acetate Chemical compound C1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C(C)=C1 RGVBNBFNSBMXID-QJPTWQEYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 238000003307 slaughter Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000005051 trimethylchlorosilane Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VDLQSPNQAVRJND-UHFFFAOYSA-N (2-methoxyphenyl) carbonochloridate Chemical compound COC1=CC=CC=C1OC(Cl)=O VDLQSPNQAVRJND-UHFFFAOYSA-N 0.000 description 1
- CCFSGQKTSBIIHG-UHFFFAOYSA-N (4-methoxyphenyl) carbonochloridate Chemical compound COC1=CC=C(OC(Cl)=O)C=C1 CCFSGQKTSBIIHG-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 1
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- SNKWLBSAKXIYKF-XUVXKRRUSA-N [(2r,3s,5r)-3-benzoyloxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl benzoate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COC(=O)C=2C=CC=CC=2)[C@@H](OC(=O)C=2C=CC=CC=2)C1 SNKWLBSAKXIYKF-XUVXKRRUSA-N 0.000 description 1
- FRQGXSIXYPMSJR-FRXPANAUSA-N [(2r,3s,5r)-5-[5-fluoro-2,4-dioxo-3-(4-propoxybenzoyl)pyrimidin-1-yl]-2-[(4-methoxyphenoxy)carbonyloxymethyl]oxolan-3-yl] (4-methoxyphenyl) carbonate Chemical compound C1=CC(OCCC)=CC=C1C(=O)N1C(=O)N([C@@H]2O[C@H](COC(=O)OC=3C=CC(OC)=CC=3)[C@@H](OC(=O)OC=3C=CC(OC)=CC=3)C2)C=C(F)C1=O FRQGXSIXYPMSJR-FRXPANAUSA-N 0.000 description 1
- VJDDQSBNUHLBTD-GGWOSOGESA-N [(e)-but-2-enoyl] (e)-but-2-enoate Chemical compound C\C=C\C(=O)OC(=O)\C=C\C VJDDQSBNUHLBTD-GGWOSOGESA-N 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VJDDQSBNUHLBTD-UHFFFAOYSA-N trans-crotonic acid-anhydride Natural products CC=CC(=O)OC(=O)C=CC VJDDQSBNUHLBTD-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
本発明は、一般式（）
（式中、R1は水素原子、アルキルカルボニル基、
アルケニルカルボニル基、アルコキシカルボニル
基、無置換の若しくは置換されたフエノキシカル
ボニル基または無置換の若しくは置換されたフエ
ニルカルボニル基を、R2は水素原子、アルキル
基、アルコキシ基、ハロゲン原子またはアルキレ
ンジオキシ基を、ｎは１または２の整数を示す。）
で表わされるＮ−アロイルチミジン誘導体および
これを使用する抗腫瘍活性物質の毒性低下剤に関
する。
本発明者等は、抗腫瘍作用を有する化合物の毒
性ないし副作用をより低減させることを目的とし
て、研究を重ねた結果、一般式（）で表わされ
る新規なＮ−アロイルチミジン誘導体が所期する
優れた作用を有し、これらを抗腫瘍作用を有する
化合物と併用すると、その抗腫瘍活性物質の毒性
ないし副作用、就中、消化管、体重及び白血球に
対する影響が軽減されることを見い出した。本発
明はかかる知見に基づくものである。
本発明に係る前記一般式（）の化合物は、抗
腫瘍作用を有する物質の毒性ないし副作用を低減
する優れた作用を有する有用な化合物である。
本発明により提供される新規化合物は、一般式
（）で表わされるＮ−アロイルチミジン誘導体
である。一般式（）において、R1で表わされ
るアルキルカルボニル基のアルキル基としては直
鎖のまたは側鎖を有するアルキル基、好ましく
は、メチル、エチル、ｎ−プロピル、イソプロピ
ル、ｎ−ブチル、イソブチル、ｔ−ブチル、ｎ−
ペンチル、イソペンチル、ｎ−ヘキシル、ｎ−ヘ
プチル、ｎ−オクチル、ｎ−ノナニル等のアルキ
ル基を、アルコキシカルボニル基のアルコキシ基
としては、直鎖のまたは側鎖を有するアルコキシ
基、好ましくは、メトキシ、エトキシ、ｎ−プロ
ポキシ、イソプロポキシ、ｎ−ブトキシ、イソブ
トキシ、ｔ−ブトキシ等のアルコキシ基を、アル
ケニルカルボニル基のアルケニル基としては、エ
テニル、１−プロペニル、２−プロペニル、１−
ブテニル、２−ブテニル、３−ブテニル等のアル
ケニル基を、置換フエノキシカルボニル基及び置
換フエニルカルボニル基の置換基としては、好ま
しくは、メチル、エチル、ｎ−プロピル、イソプ
ロピル、ｎ−ブチル、イソブチル、ｔ−ブチル等
のアルキル基、メトキシ、エトキシ、ｎ−プロポ
キシ、イソプロポキシ、ｎ−ブトキシ、イソブト
キシ、ｔ−ブトキシ等のアルコキシ基、塩素、臭
素、フツ素等のハロゲン原子を挙げることができ
る。
また、R2で表わされるアルキル基、アルコキ
シ基及びハロゲン原子としては、それぞれ上記
R1で表わされる置換フエノキシカルボニル基の
置換基として挙げたアルキル基、アルコキシ基及
びハロゲン原子と同様の基または原子を、アルキ
レンジオキシ基のアルキレン基としてはメチレ
ン、エチレン、プロピレン等のアルキレン基を挙
げることができる。
本発明の（）式の化合物は、例えば、（）
式中のR1が水素原子の場合には、チミジンを、
シリル化剤と反応させてシリル体とした後、一般
式（）
（式中、R2及びｎは前記に同義で、Ｘはハロゲ
ン原子を示す）
で表わされる酸ハロゲン化物を反応させ、次いで
脱シリル化反応を行うことにより製造することが
できる。シリル体を得る反応に使用するシリル化
剤としては、トリメチルクロルシラン、トリエチ
ルクロルシラン等を好ましく挙げることができ
る。この反応におけるシリル化剤の使用割合は、
チミジン１モルに対し２倍モル以上、好ましくは
２倍モルないし４倍モルである。この反応は、通
常、有機溶媒中、有機塩基物質の存在下に行うの
が好ましく、有機溶媒としては、アセトニトリ
ル、ジオキサン等を、有機塩基物質としてはトリ
メチルアミン、トリエチルアミン、トリブチルア
ミン、トリエチレンジアミン等の三級アルキルア
ミン、ピリジン、ピコリン等の芳香族アミンを好
ましく挙げることができる。有機塩基物質の使用
割合は、シリル化剤１モルに対し、１倍モル以上
あればよく、好ましくは１倍モルないし５倍モル
である。この反応は氷冷下ないし室温で進行し、
反時間は0.5時間ないし２時間が好ましい。
得られたシリル体と一般式（）で表わされる
酸ハロゲン化物との反応は、通常、有機溶媒中、
有機塩基物質の存在下に行うのが好ましく、酸ハ
ロゲン化物のハロゲン、としては塩素、臭素等
を、有機塩基物質としては前記シリル化反応で用
いたと同様のものを挙げることができ、有機溶媒
としては、エーテル、ジオキサン、テトラヒドロ
フラン等のエーテル類、メチルエチルケトン、ア
セトン、ジエチルケトン等のケトン類、アセトニ
トリル、ピリジン、ジメチルホルムアミド等を好
ましく挙げることができる。
この反応に使用される酸ハロゲン化物の使用割
合は、チミジン１モルに対し、１モル以上あれば
よく、好ましくは1.3倍モルないし６倍モルであ
り、有機塩基物質の使用割合は、酸ハロゲン化物
１モルに対し、１モル以上あればよく、好ましく
は１モルないし６倍モルである。
この反応は室温で進行するが所望により、加温
することにより、より反応の進行を早めることが
でき、反応時間は0.5時間ないし２時間で充分で
ある。
次に、前述した脱シリル化反応は、メタノー
ル、エタノール、プロパノール等の溶媒中、好ま
しくは酢酸、塩酸、臭酸等の酸の存在下に、通常
の方法で行うことができ、反応は室温で進行し、
反応温度は0.5時間ないし１時間で充分である。
一方、（）式中のR1が水素原子以外の基である
場合には、本発明の（）式の化合物は、チミジ
ンに一般式（）
R1Y （）
（式中、R1は前記した意味を有し、Ｙはハロゲ
ン原子を示す。）
または、一般式（）
R1 2O （）
（式中R1は前記した意味を有する）
で表わされる酸ハロゲン化物または酸無水物を反
応させて、一般式（）
（式中、R1は前記した意味を有する）
で表わされるチミジン誘導体とし、次いでこのよ
うにして得られたチミジン誘導体に前記一般式
（）で表わされる酸ハロゲン化物を反させるこ
とにより製造することができる。
上記チミジンと一般式（）の化合物または一
般式（）で表わされる化合物との反応は、通常
塩基物質の存在下または非存在下に溶媒中で行う
のが好ましく、ここで使用される酸ハロゲン化物
のハロゲン、塩基物質及び溶媒としては前記シリ
ル体と一般式（）で表わされる酸ハロゲン化物
との反応に関して挙げたものと同様のものを挙げ
ることができる。
この反応に使用される酸ハロゲン化物及び酸無
水物の使用割合はチミジン１モルに対し、２倍モ
ル以上であればよく、好ましくは２倍モルないし
６倍モルである。
この反応は０℃ないし溶媒の沸とう温度、好ま
しくは室温ないし80℃で進行し、反応時間は0.5
時間ないし３時間で充分である。
次いで、このようにして得られた一般式（）
で表わされるチミジン誘導体と一般式（）で表
わされる酸ハロゲン化物との反応は、通常、塩基
物質の存在下に溶媒中で行うのが好ましく、ここ
で使用される塩基物質及び溶媒としては、前記シ
リル体と一般式（）で表わされる酸ハロゲン化
物との反応に関して挙げたものと同様のものを挙
げることができる。
この反応に使用される酸ハロゲン化物の使用割
合は、チミジン誘導体１モルに対し、１モル以上
であればよいが、好ましくは1.3倍モルないし６
倍モルである。反応は室温ないし溶媒の沸とう温
度、好ましくは室温ないし80℃で進行し、反応時
間は２時間ないし12時間で充分である。
このようにして生成する反応混合物中から生成
物または一般式（）で表わされる本発明の化合
物を取得する場合には、通常用いられる処理操
作、例えば抽出、クロマトグラフイー、再結晶蒸
留等の方法を用いて分離精製操作を行うことによ
つて得ることができる。
次に、一般式（）の化合物およびその製造例
を掲げる。
実施例 １
チミジン3.00ｇ（12.4ミリモル）、トリメチル
クロルシラン3.51ｇ（32.2ミリモル）をアセトニ
トリル40mlに撹拌懸濁させ、氷水で冷却下にトリ
エチルアミン6.26ｇ（62.0ミリモル）を加えた。
反応液を室温に戻して２時間撹拌した後、３−メ
チルベンゾイルクロリド2.49ｇ（16.1ミリモル）
を加えて更に１時間撹拌を継続した。析出晶を
去し、液を減圧下に濃縮した。残渣をエタノー
ル40mlに溶解した後酢酸3.00ｇ（50.0ミリモル）
を加えて30分間室温で撹拌した。反応液を減圧下
に濃縮し、タール状残渣をシリカゲルカラムクロ
マトグラフイーにより精製した（メタノール：ク
ロロホルム＝４：96で溶出）。減圧下に溶媒を留
去して３−（３−メチルベンゾイル）チミジンの
粉末3.64ｇ（81.5％）を得た。
UVスペクトル；λEtoH nax（nm）：257.5
NMRスペクトル；δ（ppm），CDCl3：
チミジン部分；1.93（ｄ，Ｊ＝１Hz，C5−
CH3）、2.31（dd，Ｊ＝５Hz，6.5Hz，C2′−Ｈ）、
2.45−2.90（ｍ，２×OH）、3.70−4.00（ｍ，
C4′−Ｈ，C5′−Ｈ）、4.35−4.60（ｍ，C3′−Ｈ）、
6.19（ｔ，Ｊ＝6.5Hz，C1′−Ｈ）、7.59（ｄ，Ｊ＝
１Hz，C6H）
ベンゾイル部分；2.39（ｓ，CH3）、7.30−7.80
（4H，ｍ）
元素分析値；C18H20N2O6・0.05CHCl3としての
計算値（％） C59.18，H5.52，N7.65
実測値（％） C59.06，H5.68，N7.49
実施例 ２〜３
実施例１と同様にして置換基（R2）oを有する
ベンゾイルクロリドを用いて第表に示す化合物
を製造した。その結果を第表に示す。
The present invention is based on the general formula () (In the formula, R 1 is a hydrogen atom, an alkylcarbonyl group,
an alkenylcarbonyl group, an alkoxycarbonyl group, an unsubstituted or substituted phenoxycarbonyl group, or an unsubstituted or substituted phenylcarbonyl group, and R 2 is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, or In the dioxy group, n represents an integer of 1 or 2. ) The present invention relates to an N-aroylthymidine derivative represented by the following formula and an agent for reducing the toxicity of an antitumor active substance using the same. As a result of repeated research aimed at further reducing the toxicity or side effects of compounds with antitumor effects, the present inventors have discovered a novel N-aroylthymidine derivative represented by the general formula (). It has been found that the toxicity and side effects of the antitumor active substance, especially the effects on the gastrointestinal tract, body weight, and white blood cells, are reduced when these substances have excellent effects and are used in combination with compounds that have antitumor activity. The present invention is based on this knowledge. The compound of the general formula () according to the present invention is a useful compound that has an excellent effect of reducing the toxicity or side effects of substances having antitumor effects. The novel compound provided by the present invention is an N-aroylthymidine derivative represented by the general formula (). In the general formula (), the alkyl group of the alkylcarbonyl group represented by R 1 is a linear or side chain alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t -butyl, n-
The alkyl group of the alkoxycarbonyl group is a straight chain or side chain alkoxy group, preferably methoxy, Alkoxy groups such as ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and alkenyl carbonyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-
Alkenyl groups such as butenyl, 2-butenyl, and 3-butenyl are preferably substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, Examples include alkyl groups such as isobutyl and t-butyl, alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and t-butoxy, and halogen atoms such as chlorine, bromine, and fluorine. . In addition, the alkyl group, alkoxy group, and halogen atom represented by R 2 are as mentioned above, respectively.
The same groups or atoms as the alkyl group, alkoxy group, and halogen atom listed as the substituent of the substituted phenoxycarbonyl group represented by R 1 can be used as the alkylene group of the alkylene dioxy group, such as alkylene such as methylene, ethylene, propylene, etc. The following groups can be mentioned. The compound of formula () of the present invention is, for example, ()
When R 1 in the formula is a hydrogen atom, thymidine is
After reacting with a silylating agent to form a silyl body, the general formula () (In the formula, R 2 and n have the same meanings as above, and X represents a halogen atom.) It can be produced by reacting an acid halide represented by the following and then carrying out a desilylation reaction. Preferred examples of the silylating agent used in the reaction to obtain the silyl compound include trimethylchlorosilane and triethylchlorosilane. The proportion of silylating agent used in this reaction is
The amount is 2 times the mole or more, preferably 2 times to 4 times the mole of thymidine. This reaction is usually preferably carried out in an organic solvent in the presence of an organic basic substance. Examples of the organic solvent include acetonitrile, dioxane, etc., and examples of the organic basic substance include trimethylamine, triethylamine, tributylamine, triethylenediamine, etc. Preferred examples include aromatic amines such as alkylamines, pyridine, and picoline. The proportion of the organic basic substance to be used may be at least 1 mole, preferably 1 to 5 moles, per 1 mole of the silylating agent. This reaction proceeds under ice cooling or at room temperature,
The reaction time is preferably 0.5 to 2 hours. The reaction between the obtained silyl compound and the acid halide represented by the general formula () is usually carried out in an organic solvent,
It is preferable to carry out the reaction in the presence of an organic basic substance, and examples of the halogen of the acid halide include chlorine, bromine, etc., examples of the organic basic substance include those used in the above-mentioned silylation reaction, and examples of the organic base substance include those used in the silylation reaction. Preferred examples include ethers such as ether, dioxane and tetrahydrofuran, ketones such as methyl ethyl ketone, acetone and diethyl ketone, acetonitrile, pyridine and dimethylformamide. The ratio of the acid halide used in this reaction should be 1 mole or more, preferably 1.3 times to 6 times the mole, per 1 mole of thymidine, and the ratio of the organic base substance used is the acid halide. The amount may be 1 mole or more, preferably 1 mole to 6 times the mole. This reaction proceeds at room temperature, but if desired, the reaction can be accelerated by heating, and a reaction time of 0.5 to 2 hours is sufficient. Next, the desilylation reaction described above can be carried out in a conventional manner in a solvent such as methanol, ethanol, or propanol, preferably in the presence of an acid such as acetic acid, hydrochloric acid, or hydrobromic acid, and the reaction is carried out at room temperature. progress,
A reaction temperature of 0.5 to 1 hour is sufficient.
On the other hand, when R 1 in the formula () is a group other than a hydrogen atom, the compound of the formula () of the present invention can be replaced with thymidine by the general formula () R 1 Y () (Y represents a halogen atom.) Or, by reacting an acid halide or acid anhydride represented by the general formula () R 1 2 O () (wherein R 1 has the above meaning) Let, general formula () (In the formula, R 1 has the above-mentioned meaning) and then produce it by reacting the thus obtained thymidine derivative with an acid halide represented by the general formula (). I can do it. The reaction between the above thymidine and the compound represented by the general formula () or the compound represented by the general formula () is preferably carried out in a solvent in the presence or absence of a basic substance, and the acid halide used here As the halogen, basic substance and solvent, the same ones as those mentioned in connection with the reaction between the silyl compound and the acid halide represented by the general formula () can be mentioned. The ratio of the acid halide and acid anhydride used in this reaction may be at least 2 times the mole, preferably 2 times to 6 times the mole of thymidine. This reaction proceeds at 0°C to the boiling temperature of the solvent, preferably room temperature to 80°C, and the reaction time is 0.5°C.
An hour to three hours is sufficient. Then, the general formula () obtained in this way
The reaction between the thymidine derivative represented by the formula () and the acid halide represented by the general formula () is usually preferably carried out in a solvent in the presence of a basic substance, and the basic substance and solvent used here include the above-mentioned The same compounds as those mentioned regarding the reaction between the silyl compound and the acid halide represented by the general formula () can be mentioned. The ratio of the acid halide used in this reaction may be 1 mol or more per 1 mol of the thymidine derivative, but preferably 1.3 to 6 mol.
It is twice the mole. The reaction proceeds at room temperature to the boiling temperature of the solvent, preferably room temperature to 80°C, and a reaction time of 2 to 12 hours is sufficient. In order to obtain the product or the compound of the present invention represented by the general formula () from the reaction mixture thus produced, commonly used processing operations such as extraction, chromatography, recrystallization distillation, etc. It can be obtained by performing separation and purification operations using. Next, compounds of general formula () and production examples thereof are listed. Example 1 3.00 g (12.4 mmol) of thymidine and 3.51 g (32.2 mmol) of trimethylchlorosilane were stirred and suspended in 40 ml of acetonitrile, and 6.26 g (62.0 mmol) of triethylamine was added while cooling with ice water.
After returning the reaction solution to room temperature and stirring for 2 hours, 2.49 g (16.1 mmol) of 3-methylbenzoyl chloride was added.
was added and stirring was continued for an additional hour. The precipitated crystals were removed, and the liquid was concentrated under reduced pressure. After dissolving the residue in 40 ml of ethanol, add 3.00 g (50.0 mmol) of acetic acid.
was added and stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, and the tarry residue was purified by silica gel column chromatography (eluted with methanol:chloroform=4:96). The solvent was distilled off under reduced pressure to obtain 3.64 g (81.5%) of 3-(3-methylbenzoyl)thymidine powder. UV spectrum; λ EtoH nax (nm): 257.5 NMR spectrum; δ (ppm), CDCl 3 : Thymidine moiety; 1.93 (d, J=1Hz, C 5 −
CH 3 ), 2.31 (dd, J=5Hz, 6.5Hz, C 2 ′-H),
2.45−2.90 (m, 2×OH), 3.70−4.00 (m,
C 4 ′-H, C 5 ′-H), 4.35-4.60 (m, C 3 ′-H),
6.19 (t, J = 6.5Hz, C 1 '-H), 7.59 (d, J =
1Hz, C 6 H) Benzoyl moiety; 2.39 (s, CH 3 ), 7.30−7.80
(4H, m) Elemental analysis value; Calculated value as C 18 H 20 N 2 O 6・0.05CHCl 3 (%) C59.18, H5.52, N7.65 Actual value (%) C59.06, H5. 68, N7.49 Examples 2 to 3 The compounds shown in Table 1 were produced in the same manner as in Example 1 using benzoyl chloride having a substituent (R 2 ) o . The results are shown in Table 1.
【表】
実施例 ４
ピリジン100mlにチミジン7.60ｇ（31.4ミリモ
ル）、無水酢酸9.61ｇ（94.2ミリモル）を加え70
℃に1.5時間加熱した。反応液を減圧下に濃縮し、
油状残渣にエーテルを加えると結晶化した。結晶
を取して8.94ｇ（87.3％）の3′，5′−ジ−Ｏ−
アセチルチミジンを得た。次いでジオキサン50ml
に上記で得た3′，5′−ジ−Ｏ−アセチルチミジン
5.00ｇ（15.3ミリモル）及びトリエチルアミン
2.23ｇ（22.1ミリモル、２−メチルベンゾイルク
ロリド2.85ｇ（18.4ミリモル）を加え室温で２時
間撹拌後70℃に５時間加熱した。トリエチルアミ
ン1.52ｇ（15.0ミリモル）、２−メチルベンゾイ
ルクロリド1.89ｇ（12.2ミリモル）を追加して更
に５時間加熱した。反応液を氷水300mlに注ぎ撹
拌洗浄後、水層を除き、油状残渣を酢酸エチル
200mlに溶解して飽和食塩水で洗浄した。酢酸エ
チル層をNa2SO4で乾燥した後減圧下に溶媒を留
去して得られた残渣をシリカゲルカラムクロマト
グラフイー（クロロホルムで溶出）により精製し
た。減圧下に溶媒を留去して3.96ｇの粉末を得
た。エタノールから結晶化させて3.35ｇ（49.3
％）の3′，5′−ジ−Ｏ−アセチル−３−（２−メ
チルベンゾイル）チミジンを得た。融点：114−
115℃。
UVスペクトル；λEtOH nax（nm）：257.5
NMRスペクトル；δ（ppm），CDCl3：
チミジン部分；1.97（ｓ，C5−CH3）、2.08（ｓ，
CH3CO）、2.14（ｓ，CH3CO）、2.4付近（ｍ，
C2′−Ｈ）、4.15−4.45（ｍ，C4′−Ｈ，C5′−Ｈ）、
5.10−5.30（ｍ，C3′−Ｈ）、6.30（dd，Ｊ＝８Hz，
６Hz，C1′−Ｈ）、7.10−7.70に重なる（C6−Ｈ）
ベンゾイル部分；2.70（ｓ，CH3）、7.10−7.70
（ｍ，C3−Ｈ，C4−Ｈ，C5−Ｈ）、7.80−8.00
（ｍ，C6−Ｈ）
元素分析値：C22H24N2O8としての
計算値（％） C59.46，H5.44，N6.30
実測値（％） C59.51，H5.35，N6.29
実施例 ５〜８
実施例４と同様の操作を用いて第表に示す実
施例５ないし８の化合物を製造した。その結果を
第表に示す。[Table] Example 4 Add 7.60 g (31.4 mmol) of thymidine and 9.61 g (94.2 mmol) of acetic anhydride to 100 ml of pyridine.
℃ for 1.5 hours. Concentrate the reaction solution under reduced pressure,
The oily residue crystallized upon addition of ether. After removing the crystals, 8.94g (87.3%) of 3',5'-di-O-
Acetylthymidine was obtained. Then 50ml of dioxane
3′,5′-di-O-acetylthymidine obtained above
5.00g (15.3 mmol) and triethylamine
2.23 g (22.1 mmol), 2-methylbenzoyl chloride 2.85 g (18.4 mmol) were added, stirred at room temperature for 2 hours, and then heated to 70°C for 5 hours. Triethylamine 1.52 g (15.0 mmol), 2-methylbenzoyl chloride 1.89 g (12.2 mmol) and heated for further 5 hours.The reaction solution was poured into 300 ml of ice water and washed with stirring.The aqueous layer was removed and the oily residue was dissolved in ethyl acetate.
It was dissolved in 200ml and washed with saturated saline. After drying the ethyl acetate layer over Na 2 SO 4 , the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with chloroform). The solvent was distilled off under reduced pressure to obtain 3.96 g of powder. Crystallized from ethanol, 3.35g (49.3
%) of 3',5'-di-O-acetyl-3-(2-methylbenzoyl)thymidine was obtained. Melting point: 114−
115℃. UV spectrum; λ EtOH nax (nm): 257.5 NMR spectrum; δ (ppm), CDCl3 : Thymidine moiety; 1.97 (s, C5 - CH3 ), 2.08 (s,
CH 3 CO), 2.14 (s, CH 3 CO), around 2.4 (m,
C 2 ′-H), 4.15-4.45 (m, C 4 ′-H, C 5 ′-H),
5.10−5.30 (m, C 3 ′−H), 6.30 (dd, J=8Hz,
6Hz, C 1 ′-H), overlaps with 7.10-7.70 (C 6 -H) Benzoyl moiety; 2.70 (s, CH 3 ), 7.10-7.70
(m, C3 -H, C4 -H, C5 -H), 7.80-8.00
(m, C 6 −H) Elemental analysis value: Calculated value (%) as C 22 H 24 N 2 O 8 C59.46, H5.44, N6.30 Actual value (%) C59.51, H5.35 , N6.29 Examples 5 to 8 Using the same procedure as in Example 4, the compounds of Examples 5 to 8 shown in Table 1 were prepared. The results are shown in Table 1.
【表】【table】
【表】
実施例 ９
ジオキサン40mlに実施例１と同様の操作により
得られた3′，5′−ジ−Ｏ−アセチルチミジン1.50
ｇ（4.60ミリモル）及びトリエチルアミン2.88ml
（20.6ミリモル）、ペンゾイルクロリド1.95ｇ
（13.8ミリモル）を加えて70℃に３時間加熱した。
トリエチルアミン2.0ml（14.4ミリモル）、ベンゾ
イルクロリド1.30ｇ（9.22ミリモル）を加えて70
℃に３時間加熱を継続した。反応液を減圧下に濃
縮して、残渣を酢酸エチル150mlに溶解して飽和
食塩水で洗浄した。酢酸エチル溶液をNa2SO4で
乾燥した後、減圧下に溶媒を留去して得られた残
渣をシリカゲルカラムクロマトグラフイー（クロ
ロホルムで溶出）により精製した。減圧下に溶媒
を留去して1.59ｇ（80.4％）の3′，5′−ジ−Ｏ−
アセチル−３−ベンゾイルチミジンを粉末として
得た。
UVスペクトル；λEtOH nax（nm）：252.5
NMRスペクトル；δ（ppm），CDCl3：
チミジン部分；1.97（ｄ，Ｊ＝１Hz，C5−
CH3）、2.80（ｓ，CH3CO）、2.14（ｓ，
CH3CO）、2.4付近（ｍ，C2′−Ｈ）、4.15−4.45
（ｍ，C4′−Ｈ，C5′−Ｈ）、5.10−5.30（ｍ，
C3′−Ｈ）、6.29（dd，Ｊ＝８Hz，６Hz，C1′−
Ｈ）、7.39（ｄ，Ｊ＝１Hz，C6−Ｈ）
ベンゾイル部分；7.30−7.70（ｍ，C3−Ｈ，C4
−Ｈ，C5−Ｈ）、7.90（dd，Ｊ＝6.5Hz，２Hz，
C2−Ｈ，C6−Ｈ）
元素分析値：C21H22N2O8としての
計算値（％） C58.60，H5.15，N6.51
実測値（％） C58.34，H5.23，N6.74
実施例 10〜20
実施例９と同様の操作を用いて第表に示され
る実施例10ないし実施例20の化合物を製造した。
その結果を第表に示す。[Table] Example 9 Add 1.50 3',5'-di-O-acetylthymidine obtained by the same procedure as Example 1 to 40 ml of dioxane.
g (4.60 mmol) and triethylamine 2.88 ml
(20.6 mmol), penzoyl chloride 1.95 g
(13.8 mmol) was added and heated to 70°C for 3 hours.
70 by adding 2.0 ml (14.4 mmol) of triethylamine and 1.30 g (9.22 mmol) of benzoyl chloride.
Heating was continued for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate and washed with saturated brine. After drying the ethyl acetate solution over Na 2 SO 4 , the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with chloroform). The solvent was distilled off under reduced pressure to obtain 1.59 g (80.4%) of 3',5'-di-O-
Acetyl-3-benzoylthymidine was obtained as a powder. UV spectrum; λ EtOH nax (nm): 252.5 NMR spectrum; δ (ppm), CDCl 3 : Thymidine moiety; 1.97 (d, J=1Hz, C 5 −
CH 3 ), 2.80 (s, CH 3 CO), 2.14 (s,
CH 3 CO), around 2.4 (m, C 2 ′-H), 4.15-4.45
(m, C 4 ′-H, C 5 ′-H), 5.10-5.30 (m,
C 3 ′-H), 6.29 (dd, J=8Hz, 6Hz, C 1 ′-
H), 7.39 (d, J = 1 Hz, C 6 - H) Benzoyl moiety; 7.30 - 7.70 (m, C 3 - H, C 4
-H, C 5 -H), 7.90 (dd, J = 6.5Hz, 2Hz,
C 2 −H, C 6 −H) Elemental analysis value: Calculated value (%) as C 21 H 22 N 2 O 8 C58.60, H5.15, N6.51 Actual value (%) C58.34, H5 .23, N6.74 Examples 10 to 20 Using the same procedure as in Example 9, the compounds of Examples 10 to 20 shown in Table 1 were prepared.
The results are shown in Table 1.
【表】【table】
【表】【table】
【表】【table】
【表】
実施例 21
3′，5′−ジ−Ｏ−ベンゾイルチミジン2.00ｇ
（4.44ミリモル）をジオキサン40mlに溶解した後
３−メトキシベンゾイルクロリド3.04ｇ（17.9ミ
リモル）、トリエチルアミン4.18ml（30.0ミリモ
ル）を加え70℃に４時間加熱した。反応液を減圧
下に濃縮した後、残渣を酢酸エチル150mlに溶解
して、水、飽和食塩水で洗浄した。酸酸エチル層
を減圧下に溶媒留去し、残渣をシリカゲルカラム
クロマトグラフイー（クロロホルムで溶出）にて
精製した。油状精製物を再度酢酸エチル150mlに
溶解して希NaOH、飽和食塩水の順に洗浄した
後減圧下に溶媒を留去し、残渣を再度シリカゲル
カラムクロマトグラフイー（クロロホルムで溶
出）にて精製した。減圧下に溶媒を留去すると粉
末として1.45ｇ（55.8％）の3′，5′−ジ−Ｏ−ベ
ンゾイル−３−（３−メトキシベンゾイル）チミ
ジンを得た。
UVスペクトル；λEtOH nax（nm）：224，259.5，310
（sh）
NMRスペクトル；δ（ppm），CDCl3：
1.67（ｄ，Ｊ＝１Hz，C5−CH3）、2.5付近（ｍ，
C2′−Ｈ）、3.84（ｓ，OCH3）、4.45−4.60（ｍ，
C4′−Ｈ）、4.76（ｔ，Ｊ＝3.5Hz，C5′−Ｈ）、5.55
−5.75（ｍ，C3′−Ｈ）、6.44（dd，Ｊ＝8.5Hz，5.5
Hz，C1′−Ｈ）、7.00−7.95（ｍ，C6−Ｈ，
10aromatic−Ｈ）、7.90−8.15（ｍ，４−
aromatic−Ｈ）
元素分析値：C32H28N2O9としての
計算値（％） C65.75，H4.83，N4.79
実測値（％） C65.50，H5.00，N4.93
実施例 22
後記製造例９の如くして得られた3′，5′−ビス
−Ｏ−（４−メトキシフエノキシカルボニル）−
2′−デオキシ−５−フルオロウリジン40ｇをジオ
キサン300mlに溶解し、これに４−ｎ−プロポキ
シベンゾイルクロライト22ｇ及びトリエチルアミ
ン50mlを加えた。これを80℃で６時間撹拌下にに
放置した後、減圧下濃縮した。得られた残渣を酢
酸エチル200mlに溶解し、飽和食塩水50mlで３回
洗浄し、硫酸マグネシウムで乾燥した後、減圧下
濃縮した。得られた残留物を熱ｎ−ヘキサンで洗
浄後、酢酸エチル−エーテル−エタノールから再
結晶すると、42ｇの３−（４−ｎ−プロポキシベ
ンゾイル）−3′，5′−ビス−Ｏ−（４−メトキシフ
エノキシカルボニル）−2′−デオキシ−５−フル
オロウリジンが得られた。
収率：81％、融点：93−95℃
UVスペクトル；λEtOH nax（nm）：222.5、278（sh）、
283、291（sh）
NMRスペクトル；δ（ppm），CDCl3：ウリジン
部分、2.4付近（2H，ｍ，C2′−Ｈ）、4.30−4.58
（3H，ｍ，C4′,5′−Ｈ）、5.16−5.35（1H，ｍ，
C3′−Ｈ）、6.32（1H，bt，Ｊ＝７Hz，C1′−Ｈ）、
7.77（1H，ｄ，Ｊ＝６Hz，C6−Ｈ）；3′及び5′位
の置換基部部分、3.72（6H，ｓ，CH3O−×
２）、6.85（4H，ｄ，Ｊ＝９Hz，C3,5−Ｈ×２）、
7.08（4H，ｄ，Ｊ＝９Hz，C2,6−Ｈ×２）；３位
の置換基部分、0.99（3H，ｔ，Ｊ＝７Hz，ＣH3
CH2CH2O−）、1.50−1.96（2H，ｍ，CH3CH2
CH2O−）、3.93（2H，ｔ，Ｊ＝７Hz，
CH3CH2CH2 Ｏ−）、6.90（2H，ｄ，Ｊ＝９Hz，
C3,5−Ｈ）、7.88（2H，ｄ，Ｊ＝９Hz，C2,6−Ｈ）
元素分析値：C35H33FN2O13として
計算値（％） C59.32，H4.69，N3.95
実測値（％） C59.54，H4.75，N3.77
なお、前記実施例８，及び実施例11ないし実施
例20及び実施例22の各例において使用されるチミ
ジン誘導体はそれら自体、新規な化合物である。
以下にこれらの新規チミジン誘導体の具体的な製
造例を記載する。
製造例 １
ジオキサン50mlにチミジン3.00ｇ（12.4ミリモ
ル）、クロルギ酸４−メトキシフエニル6.96ｇ
（37.2ミリモル）を加えて撹拌懸濁液下にピリジ
ン4.39ｇ（55.5ミリモル）を加えた。添加終了後
室温３時間撹拌した後反応液を減圧下に濃縮し
た。残渣を酢酸エチル150mlに溶解して飽和食塩
水で洗浄した後、減圧下に溶媒を留去した。結晶
性残渣にエタノール50mlを加え加熱洗浄した。放
冷後結晶を取して5.70ｇ（84.8％）の3′，5′−
ビス−Ｏ−（４−メトキシフエノキシ）カルボニ
ルチミジンを得た。融点：171−172.5℃。
UVスペクトル；λEtOH nax（nm）：221，267.5
元素分析値：C26H26N2O11としての
計算値（％） C57.56，H4.83，N5.16
実測値（％） C57.70，H4.60，N5.47
製造例 ２
ピリジン30mlにチミジン3.00ｇ（12.4ミリモ
ル）、無水iso−酪酸5.88ｇ（37.2ミリモル）を加
え70℃に２時間加熱した。反応液を減圧下に濃縮
した後、油状残渣を酢酸エチル150mlに溶解して
飽和重曹水、飽和食塩水、希硫酸、飽和食塩水の
順に洗浄した。減圧下に溶媒を留去した後、油状
残渣をシリカゲルカラムクロマトグラフイーによ
り精製した（メタノール：クロロホルム＝１：99
で溶出）。油状の3′，5′−ジ−Ｏ−iso−ブタノイ
ルチミジン4.83ｇ（102％）を得た。油状物が室
温で結晶化し始めたのでイソプロピルエーテルを
加えて結晶を析出させた。融点：80−81.5℃
UVスペクトル；λEtOH nax（nm）：264
元素分析値：C18H26N2O7としての
計算値（％） C56.54，H6.85，N7.33
実測値（％） C56.32，H6.66，N7.62
製造例 ３
ピリジン30mlにチミジン3.00ｇ（12.4ミリモ
ル）、無水クロトン酸5.73ｇ（37.2ミリモル）を
加えて70℃に２時間加熱した。反応液を減圧下に
濃縮した後、残渣を酢酸エチル150mlに溶解して
希硫酸、飽和食塩水、希NaOH、飽和食塩水の
順に洗浄した。減圧下に溶媒を留去した後、残渣
をシリカゲルカラムクロマトグラフイーにより精
製した（メタノール：クロロホルム＝２：98で溶
出）。油状精製物にエーテルを加えて結晶化させ
て2.67ｇ（57％）の3′，5′−ジ−Ｏ−クロトノイ
ルチミジンを得た。融点：141.5−142.5℃
UVスペクトル；λEtOH nax（nm）：264
元素分析値：C18H22N2O7としての
計算値（％） C57.14，H5.86，N7.40
実測値（％） C56.76，H5.75，N7.39
製造例 ４
ピリジン50mlにチミジン5.00ｇ（20.7ミリモ
ル）、無水ｎ−カプロン酸13.3ｇ（62.1ミリモル）
を加え70℃に３時間加熱した。以下製造例２と同
様にして油状の3′，5′−ジ−Ｏ−ヘキサノイル−
チミジン6.02ｇ（66.2％）を得た。
UVスペクトル；λEtOH nax（nm）：264.5
元素分析値：C22H34N4O7・1/10CHCl3としての
計算値（％） C58.92，H7.63，N6.22
実測値（％） C58.89，H7.25，N6.44
製造例 ５
アセトニトリル40mlにチミジン5.00ｇ（20.7ミ
リモル）、クロル炭酸エチル5.65ｇ（51.8ミリモ
ル）を加え、続いて氷冷下にピリジン4.91ｇ
（62.2ミリモル）を加えた。添加終了後、氷冷下
で２時間、室温で12時間撹拌した。反応液を減圧
下に濃縮し、残渣を酢酸エチル150mlに溶解して
飽和食塩水で洗浄した。Na2SO4で乾燥した後、
減圧下に溶媒を留去した。結晶性残渣をシリカゲ
ルカラムクロマトグラフイーにより精製した（メ
タノール：クロロホルム＝１：99で溶出）。油状
精製物をエタノール50mlに溶解後冷却すると結晶
が析出した。これを取して3′，5′−ビス−Ｏ−
エトキシカルボニル−チミジン6.10ｇ（76.3％）
を得た。融点：148−149℃
UVスペクトル；λEtOH nax（nm）：263
元素分析値：C16H22N2O9としての
計算値（％） C49.74，H5.74，N7.25
実測値（％） C49.74，H5.70，N7.46
製造例 ６
クロル炭酸エチルの代りにクロル炭酸メチルを
用いて製造例５と同様にして3′，5′−ビス−Ｏ−
メトキシカルボニルチミジンを23.7％の収率で得
た。融点：120.5−121.5℃
UVスペクトル；λEtOH nax（nm）：263.5
元素分析値：C14H18N2O9としての
計算値（％） C46.93，H5.06，N7.82
実測値（％） C46.94，H4.97，N7.87
製造例 ７
ジオキサン50mlにチミジン3.00ｇ（12.4ミリモ
ル）、クロルギ酸イソブチル5.10ｇ（37.2ミリモ
ル）を加えた後氷水で冷却した。冷却撹拌下にピ
リジン4.39ｇ（55.5ミリモル）を加えた。冷却下
に30分間室温で2.5時間撹拌した。更に70℃に１
時間加熱した後、反応液を減圧下に濃縮した。残
渣を酢酸エチル150mlに溶解して飽和食塩水で洗
浄した後減圧下に溶媒を留去した。油状残渣を１
夜室温に放置すると結晶が析出したので、イソプ
ロピルエーテルを加えて洗浄後取して4.85ｇ
（88.5％）の3′，5′−ビス−Ｏ−イソブトキシカル
ボニルチミジンを得た。融点：128−129℃
UVスペクトル；λEtOH nax（nm）：264
元素分析値：C20H30N2O9としての
計算値（％） C54.29，H6.83，N6.33
実測値（％） C54.61，H6.65，N6.51
製造例 ８
ジオキサン30mlにチミジン3.00ｇ（12.4ミリモ
ル）、クロルギ酸フエニル5.84ｇ（37.2ミリモル）
を加え、撹拌下にピリジン3.53ｇ（44.6ミリモ
ル）を加えた。70℃に１時間加熱した後、反応液
を減圧下に濃縮した。残渣を酢酸エチル150mlに
溶解した後、飽和食塩水で洗浄した。Na2SO4で
乾燥後減圧下に溶媒を留去して得られた油状残渣
をシリカゲルカラムクロマトグラフイーにより精
した（メタノール：クロロホルム＝１：99で溶
出）。油状精製物にエーテルを加えて結晶化させ、
続いてエタノール50mlから再結晶して3′，5′−ビ
ス−Ｏ−フエノキシカルボニルチミジン3.74ｇ
（62.6％）を得た。融点：134−135℃
UVスペクトル；λEtOH nax（nm）：262.5
元素分析値：C24H22N2O9としての
計算値（％） C59.75，H4.60，N5.81
実測値（％） C59.95，H4.66，N5.90
製造例 ９
2′−デオキシ−５−フルオロウリジン2.00ｇを
乾燥ピリジン40ml中に溶解し、次いでこれに４−
メトキシフエニルクロロホルメート3.81ｇを滴下
した。
これを70℃で４時間放置した後、減圧下に濃縮
した。
このようにして得られた残渣を酢酸エチルに溶
解し、飽和食塩水で洗浄した後、硫酸マグネシウ
ムで乾燥し、減圧下に濃縮した。得られた残留物
をシリカゲルカラムクロマトグラフイー（溶媒：
２％メタノール−クロロホルム）により分画し、
画分を減圧下に濃縮すると、3′，5′−ビス−Ｏ−
（４−メトキシフエノキシカルボニル）−2′−デオ
キシ−５−フルオロウリジンが白色結晶として得
られた。
収率：73.3％、融点：189.5−191℃
UVスペクトル；λEtOH nax（nm）：221.5、269
NMRスペクトル；δ（ppm，DMSO−d6）：ウリ
ジン部分、2.44−2.65（2H，ｍ，C2′−Ｈ）、4.39
−4.64（3H，ｍ，C4′,5′−Ｈ）、5.24−5.45（1H，
ｍ，C3′−Ｈ）、6.24（1H，bt，Ｊ＝７Hz，C1′−
Ｈ）、8.02（1H，ｄ，Ｊ＝７Hz，C6−Ｈ）、11.88
（1H，bs，D2O添加で消失、−NH−）；3′及び
5′位の置換基部分、3.79（6H，ｓ，CH3O−
X2）、6.86−7.15（8H，ｍ，phenyl−Ｈ）
元素分析値：C25H23FN2O11として
計算値（％） C54.95，H4.24，N5.13
実測値（％） C55.07，H4.22，N4.94
本発明により、前記一般式（）で表わされる
Ｎ−アロイルチミジン誘導体は、これを抗腫瘍活
性物質と併用すると、当該活性物質の毒性ないし
副作用、就中、消化管、体重及び白血球に対する
影響がより軽減されるという格別の効果がもたら
される。
前記一般式（）のＮ−アロイルチミジン誘導
体を使用する対象となる抗腫瘍活性を有するピリ
ミジン誘導体としては、例えば５−フルオロウラ
シル、５−ブロモ−2′−デオキシウリジン、N1
−（２−テトラヒドロフリル−５−フルオロウラ
シル、アラビノシトシン、メソトレキセート及び
一般式（）
（式中R4は水素原子、アルキルカルボニル基ま
たは置換フエノキシカルボニル基を示し、R5は
水素原子または無置換若しくは置換フエニルカル
ボニル基を示す。）
で表わされるオルオロデオキシウリジン誘導体を
挙げることができる。ここで、一般式（）中の
R4で表わされるアルキルカルボニル基のアルキ
ル基及び置換フエノキシカルボニル基の置換基と
しては、それぞれ前記一般式（）中のR1また
はR2で表わされるアルキルカルボニル基のアル
キル基及び置換フエニルカルボニル基及び置換フ
エノキシカルボニル基の置換基として挙げたと同
様の基または原子を挙げることができ、R5で表
わされる置換フエニルカルボニル基の置換基とし
ては、前記一般式（）中のR3で表わされる置
換フエニルカルボニル基の置換基として挙げたと
同様の基または原子を挙げることができる。
また、一般式（）中のR4が無置換若しくは
置換フエノキシカルボニル基であるフルオロデオ
キシウリジン誘導体は例えば2′−デオキシ−５−
フルオロウリジンにに無置換もしくは置換フエノ
キシカルボニルクロライド類を反応させるか、
2′−デオキシ−５−フルオロウリジンにホスゲン
を反応させて得られる生成物に無置換もしくは置
換フエノール類を反応させるか、または、このよ
うにして得られた生成物に無置換もしくは置換フ
エニルカルボニルハライド類を反応させることに
よつて製造される。
抗腫瘍作用を有する化合物と一般式（）で表
わされるチミジン誘導体との使用量の割合は、抗
腫瘍作用を有する化合物１モルに対し、一般式
（）の化合物0.125倍モル以上であればよく、１
ないし２倍モルが好ましい。
抗腫瘍作用を有する化合物の臨床上の１日の投
与量は100ないし1000mgの範囲とするのが好まし
い。
抗腫瘍作用を有する化合物と一般式（）で表
わされるチミジン誘導体とは別個に投与すること
もできるが、同時に投与するのが好ましく、この
場合には、これら両化合物を予め配合しておき、
これを投与するのが好ましい。
また投与経路は治療目的によつて異なるが、通
常静脈内投与、腹腔内投与、坐剤による直腸内投
与の如き非経口的投与、または経口的投与を挙げ
ることができる。
投与の剤形としては、抗腫瘍作用を有する化合
物及び一般式（）で表わされるチミジン誘導体
につき各々の単位宛25mgないし300mg及び10mgな
いし1000mgを成分として含有する錠剤、カプセル
剤あるいは注射剤等が挙げられる。
本発明によつて提供される毒性低下剤につき、
以下に述べる如くその抗腫瘍活性及び毒性の測定
実験を行ない、これら実験結果に基づき、その治
療係数を求めた。
１ ザルコーマ180における抗腫瘍活性および毒
性測定の試験
(1) 抗腫瘍作用を有する化合物と一般式（）
で表わされるチミジン誘導体を同時に経口投
与した系での試験
(a) 抗腫瘍活性測定の試験
ザルコーマ180腫瘍細胞（ICR系雄性マ
ウスの腹腔内に継代培養されているもの）
の約1000万個を５週齢のICR系雄性マウス
の鼠径部皮下に移植した。24時間後に、後
記の第表及び第表中に示す割合で抗腫
瘍作用を有する化合物とチミジン誘導体と
を配合したものを５％アカジヤ水溶液また
は１％ツイーン80−生理食塩水のみを、各
動物宛0.1ml／10ｇの同一容量で、１日１
回、７日間、経口ゾンデにより投与し、連
日、投与直前に各動物の体重を測定した。
抗腫瘍作用を有する化合物の投与量は、
個々の化合物により異なるが、概ね、４
mg／Kgないし256mg／Kgの範囲であり、抗
腫瘍作用を有する化合物のみ及び抗腫瘍作
用を有する化合物に本発明のチミジン誘導
体を配合した場合には、配合モル比を１：
0.125ないし１：20として、同一化合物に
つき、投与量を１ないし４段階にわたり変
え、各投与段階毎に１群のマウス（６匹か
らなる）に投与した。尚、対照群には18匹
のマウスを用いた。
移植から８日目にマウスをエーテル麻酔
下に放血することによつて致死せしめ、そ
の腫瘍組織を摘出し、直ちに腫瘍重量を測
定した。個々の化合物につき、投与量毎
に、腫瘍重量の平均値（これをＴとする）
及び対照群における腫瘍重量の平均値（こ
れをＣとする）をそれぞれ求め用量作用曲
線よりＴ／Ｃ値が0.70及び0.50を示す数値
を読みとつた。
(b) 毒性測定の試験
前記(1)−(a)の実験におけるマウスの体重
減少度及び白血球数減少度の測定及び消化
管の内容物観察を行うことによつて、毒性
測定を行つた。
(i) 体重に及ぼす影響
動物の体重は初回投与前より８日目屠
殺直前まで毎日測定した。毒性指標とし
て、８日目屠殺直前の平均体重の投与前
の平均体重に対する比を各群毎に求め、
その対照群の比に対する相対値を各用量
毎に算出し、この相対値が0.90になる用
量（BW0.9）を用量作用曲線より求め
た。
更に、抗腫瘍活性と毒性との関係を知
るために、治療係数としてBW0.9とＴ／
Ｃ：0.70及びＴ／Ｃ：0.50との比
（BW0.9／Ｔ／Ｃ：7.70，BW0.9／Ｔ／
Ｃ：0.50）を求めた。
また、用量作用曲線を求めない場合に
は、８日目屠殺直前の平均体重の投与前
の平均体重に対する比を各群毎に求め、
その対照群の比に対する相対値（BW）
をＴ／Ｃの値で除した数値（BW／Ｔ／
Ｃ）を治療係数として求めた。
(ii) 白血球数に及ぼす影響
８日目屠殺時に採血した血中の白血
球数を、トーア自動血球計数装置・モデ
ルCC−108を用いて測定し、対照群の白
血球数の30％を示す用量（Ｌ／Ｃ：
0.30）を用量作用曲線より求めた。
更に、抗腫瘍活性と骨髄への毒性との
関係を知るために、治療係数としてＬ／
Ｃ：0.30とＴ／Ｃ：0.70及びＴ／Ｃ：
0.50との比（Ｌ／Ｃ：0.30／Ｔ／Ｃ：
0.70，Ｌ／Ｃ：0.30／Ｔ／Ｃ：0.50）を
求めた。
また、用量作用曲線を求めない場合に
は、対照群の白血球数に対する比（Ｌ／
Ｃ）をＴ／Ｃで除した数値（Ｌ／Ｃ／
Ｔ／Ｃ）を治療係数として求めた。
(iii) 消化管に及ぼす影響
動物を８日目に、腫瘍の摘出後に開腹
し、消化管の障害を肉眼的に観察するこ
とにより、下記の基準に従い消化管に及
ぼす影響を測定した。
消化管障害指数の基準
小腸内容物；
水様性ではあるが軽度な場合 １点
水様性であり内容物を殆ど含まない場合
２点
盲腸便の状態；
泥状であるが水分含量の多い場合 １点
水様性であり内容物が少ない場合 ２点
結腸・直腸便の状態；
軟便（排泄直前の便） １点
下痢便で内容物を含む場合 ２点
水様便で内容物を殆ど含まない場合 ３点
各固体における小腸、盲腸、結腸及び
直腸に関する指数の和をもつて、その固
体の障害指数とする。従つて最も激しい
障害が観察された固体では、指数は７点
となる。
消化管障害指数が２および３点を示す
用量（G2およびG3）を用量作用曲線よ
り求めた。
更に、抗腫瘍活性と消化管への障害と
の関係を知るために、治療係数として、
G2とＴ／Ｃ：0.70およびＴ／Ｃ：0.50と
の比（G2／Ｔ／Ｃ：0.70，G2／Ｔ／
Ｃ：0.50）およびG3とＴ／Ｃ：0.70およ
びＴ／Ｃ：0.50との比（G3／Ｔ／Ｃ：
0.70，G3／Ｔ／Ｃ：0.50）を求めた。
G2，G3を求めない場合には、最も激
しい障害を示す指数７と実測の消化管障
害指数(G)との差をＴ／Ｃで徐した数値を
（７−Ｇ／Ｔ／Ｃ）治療係数として求め
た。
抗腫瘍活性及び毒性の結果及びこれから求め
た治療係数を第表ないし第表に示す。[Table] Example 21 3',5'-di-O-benzoylthymidine 2.00g
(4.44 mmol) was dissolved in 40 ml of dioxane, then 3.04 g (17.9 mmol) of 3-methoxybenzoyl chloride and 4.18 ml (30.0 mmol) of triethylamine were added and heated to 70°C for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in 150 ml of ethyl acetate and washed with water and saturated brine. The solvent in the ethyl acid layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform). The oily purified product was again dissolved in 150 ml of ethyl acetate and washed successively with diluted NaOH and saturated brine, then the solvent was distilled off under reduced pressure, and the residue was purified again by silica gel column chromatography (eluting with chloroform). The solvent was distilled off under reduced pressure to obtain 1.45 g (55.8%) of 3',5'-di-O-benzoyl-3-(3-methoxybenzoyl)thymidine as a powder. UV spectrum; λ EtOH nax (nm): 224, 259.5, 310
(sh) NMR spectrum; δ (ppm), CDCl3 : 1.67 (d, J=1Hz, C5 - CH3 ), around 2.5 (m,
C 2 ′-H), 3.84 (s, OCH 3 ), 4.45-4.60 (m,
C 4 ′-H), 4.76 (t, J=3.5Hz, C 5 ′-H), 5.55
-5.75 (m, C 3 '-H), 6.44 (dd, J=8.5Hz, 5.5
Hz, C 1 '-H), 7.00-7.95 (m, C 6 -H,
10aromatic-H), 7.90-8.15(m, 4-
aromatic-H) Elemental analysis value: Calculated value as C 32 H 28 N 2 O 9 (%) C65.75, H4.83, N4.79 Actual value (%) C65.50, H5.00, N4.93 Example 22 3',5'-bis-O-(4-methoxyphenoxycarbonyl)- obtained as in Production Example 9 below
40 g of 2'-deoxy-5-fluorouridine was dissolved in 300 ml of dioxane, and 22 g of 4-n-propoxybenzoyl chlorite and 50 ml of triethylamine were added thereto. This was left under stirring at 80°C for 6 hours, and then concentrated under reduced pressure. The resulting residue was dissolved in 200 ml of ethyl acetate, washed three times with 50 ml of saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hot n-hexane and then recrystallized from ethyl acetate-ether-ethanol to give 42 g of 3-(4-n-propoxybenzoyl)-3',5'-bis-O-(4 -methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained. Yield: 81%, melting point: 93-95℃ UV spectrum: λ EtOH nax (nm): 222.5, 278 (sh),
283, 291 (sh) NMR spectrum; δ (ppm), CDCl 3 : Uridine moiety, around 2.4 (2H, m, C 2 '-H), 4.30-4.58
(3H, m, C 4 ′ ,5 ′−H), 5.16−5.35 (1H, m,
C 3 ′-H), 6.32 (1H, bt, J=7Hz, C 1 ′-H),
7.77 (1H, d, J = 6 Hz, C 6 −H); substituent moiety at 3′ and 5′ positions, 3.72 (6H, s, CH 3 O−×
2), 6.85 (4H, d, J = 9Hz, C 3,5 −H × 2),
7.08 (4H, d, J = 9 Hz, C 2,6 -H x 2); 3rd-position substituent part, 0.99 (3H, t, J = 7 Hz, C H 3
CH 2 CH 2 O−), 1.50−1.96 (2H, m, CH 3 C H 2
CH 2 O−), 3.93 (2H, t, J = 7Hz,
CH 3 CH 2 C H 2 O-), 6.90 (2H, d, J=9Hz,
C 3,5 −H), 7.88 (2H, d, J = 9Hz, C 2,6 −H) Elemental analysis value: C 35 H 33 FN 2 O 13 Calculated value (%) C59.32, H4.69 , N3.95 Actual value (%) C59.54, H4.75, N3.77 The thymidine derivatives used in each of the above-mentioned Example 8, Examples 11 to 20, and Example 22 are It is itself a new compound.
Specific production examples of these new thymidine derivatives are described below. Production example 1 3.00 g (12.4 mmol) of thymidine and 6.96 g of 4-methoxyphenyl chloroformate in 50 ml of dioxane
(37.2 mmol) and 4.39 g (55.5 mmol) of pyridine was added to the stirred suspension. After the addition was completed, the reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 150 ml of ethyl acetate, washed with saturated brine, and then the solvent was distilled off under reduced pressure. 50 ml of ethanol was added to the crystalline residue and washed with heat. After cooling, remove the crystals and obtain 5.70 g (84.8%) of 3', 5'-
Bis-O-(4-methoxyphenoxy)carbonylthymidine was obtained. Melting point: 171-172.5℃. UV spectrum; λ EtOH nax (nm): 221, 267.5 Elemental analysis value: Calculated value as C 26 H 26 N 2 O 11 (%) C57.56, H4.83, N5.16 Actual value (%) C57. 70, H4.60, N5.47 Production Example 2 3.00 g (12.4 mmol) of thymidine and 5.88 g (37.2 mmol) of iso-butyric anhydride were added to 30 ml of pyridine and heated to 70°C for 2 hours. After concentrating the reaction solution under reduced pressure, the oily residue was dissolved in 150 ml of ethyl acetate and washed successively with saturated aqueous sodium bicarbonate, saturated brine, dilute sulfuric acid, and saturated brine. After distilling off the solvent under reduced pressure, the oily residue was purified by silica gel column chromatography (methanol:chloroform=1:99).
). 4.83 g (102%) of oily 3',5'-di-O-iso-butanoylthymidine was obtained. Since the oil started to crystallize at room temperature, isopropyl ether was added to precipitate crystals. Melting point: 80-81.5℃ UV spectrum: λ EtOH nax (nm): 264 Elemental analysis value: Calculated value as C 18 H 26 N 2 O 7 (%) C56.54, H6.85, N7.33 Actual value ( %) C56.32, H6.66, N7.62 Production Example 3 3.00 g (12.4 mmol) of thymidine and 5.73 g (37.2 mmol) of crotonic anhydride were added to 30 ml of pyridine and heated at 70°C for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in 150 ml of ethyl acetate and washed successively with dilute sulfuric acid, saturated brine, dilute NaOH, and saturated brine. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methanol:chloroform=2:98). Ether was added to the oily product for crystallization to obtain 2.67 g (57%) of 3',5'-di-O-crotonoylthymidine. Melting point: 141.5-142.5℃ UV spectrum: λ EtOH nax (nm): 264 Elemental analysis value: Calculated value as C 18 H 22 N 2 O 7 (%) C57.14, H5.86, N7.40 Actual value ( %) C56.76, H5.75, N7.39 Production example 4 50 ml of pyridine, 5.00 g (20.7 mmol) of thymidine, 13.3 g (62.1 mmol) of n-caproic anhydride
was added and heated to 70°C for 3 hours. In the same manner as in Production Example 2, oily 3',5'-di-O-hexanoyl-
6.02g (66.2%) of thymidine was obtained. UV spectrum; λ EtOH nax (nm): 264.5 Elemental analysis value: Calculated value as C22H34N4O7 ・1/ 10CHCl3 (%) C58.92, H7.63, N6.22 Actual value (% ) ) C58.89, H7.25, N6.44 Production example 5 Add 5.00 g (20.7 mmol) of thymidine and 5.65 g (51.8 mmol) of ethyl chlorocarbonate to 40 ml of acetonitrile, then add 4.91 g of pyridine under ice cooling.
(62.2 mmol) was added. After the addition was completed, the mixture was stirred for 2 hours under ice cooling and for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate and washed with saturated brine. After drying with Na2SO4 ,
The solvent was distilled off under reduced pressure. The crystalline residue was purified by silica gel column chromatography (eluted with methanol:chloroform=1:99). When the oily purified product was dissolved in 50 ml of ethanol and cooled, crystals were precipitated. Taking this, 3′,5′-bis-O-
Ethoxycarbonyl-thymidine 6.10g (76.3%)
I got it. Melting point: 148-149℃ UV spectrum: λ EtOH nax (nm): 263 Elemental analysis value: Calculated value as C 16 H 22 N 2 O 9 (%) C49.74, H5.74, N7.25 Actual value ( %) C49.74, H5.70, N7.46 Production Example 6 3′,5′-bis-O-
Methoxycarbonylthymidine was obtained with a yield of 23.7%. Melting point: 120.5-121.5℃ UV spectrum: λ EtOH nax (nm): 263.5 Elemental analysis value: Calculated value as C 14 H 18 N 2 O 9 (%) C46.93, H5.06, N7.82 Actual value ( %) C46.94, H4.97, N7.87 Production Example 7 After adding 3.00 g (12.4 mmol) of thymidine and 5.10 g (37.2 mmol) of isobutyl chloroformate to 50 ml of dioxane, the mixture was cooled with ice water. While cooling and stirring, 4.39 g (55.5 mmol) of pyridine was added. Stirred under cooling for 30 minutes and at room temperature for 2.5 hours. Further to 70℃ 1
After heating for an hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 150 ml of ethyl acetate, washed with saturated brine, and then the solvent was distilled off under reduced pressure. 1 oily residue
When I left it at room temperature overnight, crystals precipitated, so I added isopropyl ether and washed them, then collected them and collected 4.85g.
(88.5%) of 3',5'-bis-O-isobutoxycarbonylthymidine was obtained. Melting point: 128-129℃ UV spectrum: λ EtOH nax (nm): 264 Elemental analysis value: Calculated value as C 20 H 30 N 2 O 9 (%) C54.29, H6.83, N6.33 Actual value ( %) C54.61, H6.65, N6.51 Production example 8 3.00 g (12.4 mmol) of thymidine and 5.84 g (37.2 mmol) of phenyl chloroformate in 30 ml of dioxane
was added, and 3.53 g (44.6 mmol) of pyridine was added with stirring. After heating to 70°C for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 150 ml of ethyl acetate, and then washed with saturated brine. After drying over Na 2 SO 4 , the solvent was distilled off under reduced pressure, and the resulting oily residue was purified by silica gel column chromatography (eluted with methanol:chloroform = 1:99). Add ether to the oily refined product to crystallize it,
Subsequently, recrystallization from 50 ml of ethanol yielded 3.74 g of 3',5'-bis-O-phenoxycarbonylthymidine.
(62.6%). Melting point: 134-135℃ UV spectrum: λ EtOH nax (nm): 262.5 Elemental analysis value: Calculated value as C 24 H 22 N 2 O 9 (%) C59.75, H4.60, N5.81 Actual value ( %) C59.95, H4.66, N5.90 Production Example 9 2.00 g of 2'-deoxy-5-fluorouridine was dissolved in 40 ml of dry pyridine, and then 4-
3.81 g of methoxyphenyl chloroformate was added dropwise. This was left at 70°C for 4 hours and then concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (solvent:
2% methanol-chloroform),
The fractions were concentrated under reduced pressure to give 3′,5′-bis-O-
(4-Methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained as white crystals. Yield: 73.3%, melting point: 189.5-191℃ UV spectrum; λ EtOH nax (nm): 221.5, 269 NMR spectrum; δ (ppm, DMSO- d6 ): uridine moiety, 2.44-2.65 (2H, m, C 2′ -H), 4.39
−4.64 (3H, m, C 4 ′ ,5 ′−H), 5.24−5.45 (1H,
m, C 3 ′-H), 6.24 (1H, bt, J=7Hz, C 1 ′-
H), 8.02 (1H, d, J=7Hz, C6 -H), 11.88
(1H, bs, disappeared by addition of D 2 O, −NH−); 3′ and
Substituent moiety at position 5′, 3.79 (6H, s, CH 3 O−
X2), 6.86-7.15 (8H, m, phenyl-H) Elemental analysis value: C 25 H 23 FN 2 O 11 Calculated value (%) C54.95, H4.24, N5.13 Actual value (%) C55 .07, H4.22, N4.94 According to the present invention, when the N-aroylthymidine derivative represented by the general formula () is used in combination with an antitumor active substance, the toxicity or side effects of the active substance, especially , the effects on the gastrointestinal tract, body weight, and white blood cells are further reduced. Examples of pyrimidine derivatives having antitumor activity for which the N-aroylthymidine derivative of general formula () is used include 5-fluorouracil, 5-bromo-2'-deoxyuridine, N 1
-(2-tetrahydrofuryl-5-fluorouracil, arabinocytosine, methotrexate and general formula () (In the formula, R 4 represents a hydrogen atom, an alkylcarbonyl group, or a substituted phenoxycarbonyl group, and R 5 represents a hydrogen atom or an unsubstituted or substituted phenylcarbonyl group.) be able to. Here, in the general formula ()
The alkyl group and substituted phenoxycarbonyl group of the alkyl carbonyl group represented by R 4 are the alkyl group and substituted phenyl group of the alkyl carbonyl group represented by R 1 or R 2 in the general formula (), respectively. The same groups or atoms listed as substituents for the carbonyl group and substituted phenoxycarbonyl group can be mentioned, and as the substituent for the substituted phenylcarbonyl group represented by R5 , R in the general formula () above can be used. The same groups or atoms listed as substituents for the substituted phenylcarbonyl group represented by 3 can be mentioned. In addition, fluorodeoxyuridine derivatives in which R 4 in the general formula () is an unsubstituted or substituted phenoxycarbonyl group are, for example, 2'-deoxy-5-
Reacting fluorouridine with unsubstituted or substituted phenoxycarbonyl chloride, or
The product obtained by reacting 2'-deoxy-5-fluorouridine with phosgene is reacted with unsubstituted or substituted phenols, or the product thus obtained is reacted with unsubstituted or substituted phenylcarbonyl. Manufactured by reacting halides. The ratio of the amount of the compound having an antitumor effect to the thymidine derivative represented by the general formula () may be at least 0.125 times the mole of the compound of the general formula () per 1 mole of the compound having an antitumor effect; 1
Preferably, the amount is 2 to 2 times the mole amount. The daily clinical dose of the compound having antitumor activity is preferably in the range of 100 to 1000 mg. Although the compound having an antitumor effect and the thymidine derivative represented by the general formula () can be administered separately, it is preferable to administer them at the same time. In this case, these two compounds are blended in advance,
Preferably, this is administered. The route of administration varies depending on the therapeutic purpose, but usually includes intravenous administration, intraperitoneal administration, parenteral administration such as intrarectal administration using suppositories, or oral administration. Examples of dosage forms for administration include tablets, capsules, and injections containing 25 mg to 300 mg and 10 mg to 1000 mg of the compound having antitumor activity and the thymidine derivative represented by the general formula () as ingredients. It will be done. Regarding the toxicity reducing agent provided by the present invention,
As described below, experiments were conducted to measure its antitumor activity and toxicity, and its therapeutic index was determined based on the results of these experiments. 1 Test for antitumor activity and toxicity measurement in Sarcoma 180 (1) Compounds with antitumor activity and general formula ()
Test in a system in which the thymidine derivative represented by was simultaneously orally administered (a) Test for measuring antitumor activity Sarcoma 180 tumor cells (subcultured intraperitoneally in ICR male mice)
Approximately 10 million cells were transplanted subcutaneously into the inguinal region of 5-week-old male ICR mice. After 24 hours, a 5% Acadia aqueous solution or a 1% Tween 80-physiological saline solution containing a compound with antitumor activity and a thymidine derivative in the proportions shown in Tables 1 and 2 below was administered to each animal. Same volume of 0.1ml/10g, once a day
The animals were administered by oral probe twice for 7 days, and the weight of each animal was measured every day immediately before administration.
The dose of the compound with antitumor activity is
Although it varies depending on the individual compound, in general, 4
mg/Kg to 256 mg/Kg, and when the thymidine derivative of the present invention is blended only with a compound having an antitumor effect or with a compound having an antitumor effect, the blending molar ratio is 1:
Doses were varied from 0.125 to 1:20 over 1 to 4 steps for the same compound, and one group of mice (consisting of 6 mice) was administered at each dose step. In addition, 18 mice were used as a control group. On the 8th day after transplantation, the mouse was sacrificed by exsanguination under ether anesthesia, the tumor tissue was excised, and the tumor weight was immediately measured. Average tumor weight for each dose of each compound (this is defined as T)
The average tumor weight (this is referred to as C) in the control group and the control group was determined, and the values indicating T/C values of 0.70 and 0.50 were read from the dose-response curve. (b) Test for measuring toxicity Toxicity was measured by measuring the degree of weight loss and decrease in white blood cell count of the mice in the experiment (1)-(a) above, and observing the contents of the gastrointestinal tract. (i) Effect on body weight Animal body weights were measured daily from before the first administration until just before sacrifice on the 8th day. As a toxicity index, the ratio of the average body weight immediately before slaughter on the 8th day to the average body weight before administration was determined for each group.
The relative value to the ratio of the control group was calculated for each dose, and the dose (BW 0.9 ) at which this relative value was 0.90 was determined from the dose-response curve. Furthermore, in order to understand the relationship between antitumor activity and toxicity, BW 0.9 and T/
Ratio of C: 0.70 and T/C: 0.50 (BW 0.9 /T/C: 7.70, BW 0.9 /T/
C: 0.50) was calculated. In addition, if a dose-response curve is not determined, the ratio of the average body weight immediately before slaughter on the 8th day to the average body weight before administration is determined for each group.
Relative value to that control group ratio (BW)
is divided by the T/C value (BW/T/
C) was determined as a therapeutic coefficient. (ii) Effect on white blood cell count The number of white blood cells in the blood collected at the time of sacrifice on the 8th day was measured using a TOA automatic blood cell counter, model CC-108. L/C:
0.30) was determined from the dose-effect curve. Furthermore, in order to understand the relationship between antitumor activity and bone marrow toxicity, L/
C: 0.30 and T/C: 0.70 and T/C:
Ratio with 0.50 (L/C: 0.30/T/C:
0.70, L/C: 0.30/T/C: 0.50). In addition, if a dose-response curve is not determined, the ratio (L/
C) divided by T/C (L/C/
T/C) was determined as a therapeutic coefficient. (iii) Effect on the gastrointestinal tract On the 8th day, the animals were subjected to laparotomy after tumor removal, and damage to the gastrointestinal tract was visually observed to determine the effect on the gastrointestinal tract according to the following criteria. Standard small intestine contents for gastrointestinal disorder index: Watery but mild 1 point Watery with almost no contents
2 points Condition of cecal stool: muddy but with high water content 1 point Watery and low content 2 points Condition of colon/rectal stool; Soft stool (stool just before defecation) 1 point Diarrhea stool If the stool contains contents: 2 points If the stool is watery and contains almost no contents: 3 points The sum of the indices for the small intestine, caecum, colon, and rectum for each individual is the disability index for that individual. Therefore, for the individual in which the most severe disturbance was observed, the index would be 7 points. The doses (G 2 and G 3 ) giving the gastrointestinal disorder index points of 2 and 3 were determined from the dose-effect curve. Furthermore, in order to understand the relationship between antitumor activity and damage to the gastrointestinal tract, as a therapeutic coefficient,
The ratio of G 2 to T/C: 0.70 and T/C: 0.50 (G 2 /T/C: 0.70, G 2 /T/
C: 0.50) and the ratio of G 3 to T/C: 0.70 and T/C: 0.50 (G 3 /T/C:
0.70, G 3 /T/C: 0.50). If G 2 and G 3 are not calculated, use the difference between index 7, which indicates the most severe disorder, and the actual gastrointestinal disorder index (G), divided by T/C (7-G/T/C). It was calculated as a treatment coefficient. The results of antitumor activity and toxicity and the therapeutic index calculated from the results are shown in Tables 1 and 2.
【表】【table】
【表】
表中、（R2）oの項でR3とあるは、一般式
（）中、[Table] In the table, R 3 in the term (R 2 ) o means in the general formula (),
【式】がＨであ
る化合物を示す。
(2) 抗腫瘍作用を有する化合物と一定用量の一
般式（）で表わされるチミジン誘導体を同
時に経口投与した系での試験
(a) 抗腫瘍活性測定の試験
前記(1)−(a)における抗腫瘍作用を有する
化合物とと一定用量の一般式（）で表わ
されるチミジン誘導体を同時に投与し、(1)
−(a)と同様にして、抗腫瘍活性測定の試験
を行つた。
(b) 毒性測定の試験
前記(2)−(a)の実験におけるマウスの体重
減少度、白血球数減少度及び消化管障害度
を(1)−(b)の方法と同様にして測定すること
によつて、毒性測定の試験を行ない、治療
係数を求めた。
抗腫瘍活性及び毒性測定の結果を第表
に、これから求めた治療係数を第表に示
す。[Formula] represents a compound in which H is H. (2) Test in a system in which a compound with antitumor activity and a fixed dose of a thymidine derivative represented by the general formula () are simultaneously administered orally (a) Test for measuring antitumor activity The antitumor activity described in (1)-(a) above A compound having tumor activity and a certain dose of a thymidine derivative represented by the general formula () are simultaneously administered, (1)
-An antitumor activity measurement test was conducted in the same manner as in (a). (b) Toxicity measurement test The degree of weight loss, decrease in white blood cell count, and degree of gastrointestinal disorder of the mice in the experiment (2)-(a) above shall be measured in the same manner as in (1)-(b). Toxicity measurement tests were conducted to determine the therapeutic index. The results of antitumor activity and toxicity measurements are shown in Table 1, and the therapeutic coefficients calculated from the results are shown in Table 1.
【表】【table】
【表】【table】
【表】
(3) 抗腫瘍作用を有する化合物と一般式（）
で表わされるチミジン誘導体の投与経路を変
えた系での試験
(a) 抗腫瘍活性測定の試験
前記(1)−(a)の実験における、抗腫瘍作用
を有する化合物とチミジン誘導体とを腹腔
内の投与に変えて、(1)−(a)と同様にして抗
腫瘍活性測定の試験を行つた。
(b) 毒性測定の試験
前記(3)−(a)の実験におけるマウスの体重
減少度、白血球数減少度及び消化管障害度
を(1)−(b)の方法と同様にして毒性測定の試
験を行い、治療係数を求めた。
抗腫瘍活性及び毒性測定の結果及び治療係
数を第表に示す。[Table] (3) Compounds with antitumor activity and general formula ()
Tests using different routes of administration of the thymidine derivative represented by Instead of administration, a test for measuring antitumor activity was conducted in the same manner as in (1)-(a). (b) Toxicity measurement test The degree of weight loss, decrease in white blood cell count, and degree of gastrointestinal disorder of the mice in the experiment (3)-(a) above were measured in the same manner as in (1)-(b). A test was conducted and a therapeutic coefficient was determined. The results of antitumor activity and toxicity measurements and therapeutic index are shown in Table 1.
【表】
第表ないし第表の試験結果から、一般式
（）の化合物を抗腫瘍活性物質と併用した場合
は抗腫瘍作用を有する化合物単剤の投与の場合に
比して、活性物質の抗腫瘍活性を減少させること
なく、消化管障害、白血球数及び体重の減少等の
毒性ないし副作用を低減し、かつ高い治療係数値
を与えることが明らかであり、本発明が、癌の実
際の治療に際して優れた有用性を有するものであ
ることが明らかに示される。[Table] From the test results in Tables 1 and 2, it can be seen that when the compound of general formula () is used in combination with an antitumor active substance, the antitumor effect of the active substance is greater than when the compound with antitumor activity is administered alone. It is clear that the present invention reduces toxicity or side effects such as gastrointestinal disorders, decreases in white blood cell count and body weight, and provides a high therapeutic index value without reducing tumor activity, and the present invention is useful in the actual treatment of cancer. It is clearly shown that it has excellent utility.
Claims (1)
アルケニルカルボニル基、アルコキシカルボニル
基、無置換の若しくは置換されたフエノキシカル
ボニル基または無置換の若しくは置換されたフエ
ニルカルボニル基を、R2は水素原子、アルキル
基、アルコキシ基、ハロゲン原子またはアルキレ
ンジオキシ基を、ｎは１または２の整数を示す。） で表わされるＮ−アロイルチミジン誘導体。 ２ R1が水素原子である特許請求の範囲第１項
記載のＮ−アロイルチミジン誘導体。 ３ R1が炭素原子数２ないし６個のアルキルカ
ルボニル基である特許請求の範囲第１項記載のＮ
−アロイルチミジン誘導体。 ４ R1が炭素原子数２ないし５個のアルコキシ
カルボニル基である特許請求の範囲第１項記載の
Ｎ−アロイルチミジン誘導体。 ５ R1がアルコキシ置換フエノキシカルボニル
基である特許請求の範囲第１項記載のＮ−アロイ
ルチミジン誘導体。 ６ R1がメチルカルボニル基、プロピルカルボ
ニル基またはペンチルカルボニル基である特許請
求の範囲第３項記載のＮ−アロイルチミジン誘導
体。 ７ R1がメトキシカルボニル基、エトキシカル
ボニル基またはブトキシカルボニル基である特許
請求の範囲第４項記載のＮ−アロイルチミジン誘
導体。 ８ R1がメトキシフエノキシカルボニル基であ
る特許請求の範囲第５項記載のＮ−アロイルチミ
ジン誘導体。 ９ R1が炭素原子数１ないし４個のアルキル基
である特許請求の範囲第１項ないし第８項のいず
れかに記載のＮ−アロイルチミジン誘導体。 １０ R2が炭素原子数１ないし４個のアルコキ
シ基である特許請求の範囲第１項ないし第８項の
いずれかに記載のＮ−アロイルチミジン誘導体。 １１ R2がメチレンジオキシ基である特許請求
の範囲第１項ないし第８項のいずれかに記載のＮ
−アロイルチミジン誘導体。 １２ R2がフツ素原子、塩素原子または臭素原
子である特許請求の範囲第１項ないし第８項のい
ずれかに記載のＮ−アロイルチミジン誘導体。 １３ 抗腫瘍活性を有するピリミジン誘導体に対
する毒性低下剤であつて、一般式、 （式中、R1は水素原子、アルキルカルボニル基、
アルケニルカルボニル基、アルコキカルボニル
基、無置換の若しくは置換されたフエノキシカル
ボニル基または無置換の若しくは置換されたフエ
ニルカルボニル基を、R2は水素原子、アルキル
基、アルコキシ基、ハロゲン原子またはアルキレ
ンジオキシ基を、ｎは１または２の整数を示す。） で表わされるＮ−アロイルチミジン誘導体を使用
することを特徴とする前記ピリミジン誘導体に対
する毒性低下剤。[Claims] 1 General formula, (In the formula, R 1 is a hydrogen atom, an alkylcarbonyl group,
an alkenylcarbonyl group, an alkoxycarbonyl group, an unsubstituted or substituted phenoxycarbonyl group, or an unsubstituted or substituted phenylcarbonyl group, and R 2 is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, or In the dioxy group, n represents an integer of 1 or 2. ) An N-aroylthymidine derivative represented by: 2. The N-aroylthymidine derivative according to claim 1, wherein R1 is a hydrogen atom. 3 N according to claim 1, wherein R 1 is an alkylcarbonyl group having 2 to 6 carbon atoms.
-Aroylthymidine derivatives. 4. The N-aroylthymidine derivative according to claim 1, wherein R1 is an alkoxycarbonyl group having 2 to 5 carbon atoms. 5. The N-aroylthymidine derivative according to claim 1, wherein R 1 is an alkoxy-substituted phenoxycarbonyl group. 6. The N-aroylthymidine derivative according to claim 3, wherein R1 is a methylcarbonyl group, a propylcarbonyl group, or a pentylcarbonyl group. 7. The N-aroylthymidine derivative according to claim 4, wherein R 1 is a methoxycarbonyl group, an ethoxycarbonyl group, or a butoxycarbonyl group. 8. The N-aroylthymidine derivative according to claim 5, wherein R 1 is a methoxyphenoxycarbonyl group. 9. The N-aroylthymidine derivative according to any one of claims 1 to 8, wherein R1 is an alkyl group having 1 to 4 carbon atoms. 10. The N-aroylthymidine derivative according to any one of claims 1 to 8, wherein R2 is an alkoxy group having 1 to 4 carbon atoms. 11 N according to any one of claims 1 to 8, wherein R 2 is a methylenedioxy group
-Aroylthymidine derivatives. 12. The N-aroylthymidine derivative according to any one of claims 1 to 8, wherein R2 is a fluorine atom, a chlorine atom, or a bromine atom. 13 A toxicity reducing agent for pyrimidine derivatives having antitumor activity, which has the general formula: (In the formula, R 1 is a hydrogen atom, an alkylcarbonyl group,
An alkenylcarbonyl group, an alkoxycarbonyl group, an unsubstituted or substituted phenoxycarbonyl group, or an unsubstituted or substituted phenylcarbonyl group, and R 2 is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, or n represents an integer of 1 or 2; ) A toxicity reducing agent for the above pyrimidine derivative, characterized in that it uses an N-aroylthymidine derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2951284A JPS60174797A (en) | 1984-02-21 | 1984-02-21 | N-aroylthymidine derivative and agent for lowering toxicity of antitumor active substance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2951284A JPS60174797A (en) | 1984-02-21 | 1984-02-21 | N-aroylthymidine derivative and agent for lowering toxicity of antitumor active substance |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60174797A JPS60174797A (en) | 1985-09-09 |
| JPH0559119B2 true JPH0559119B2 (en) | 1993-08-30 |
Family
ID=12278148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2951284A Granted JPS60174797A (en) | 1984-02-21 | 1984-02-21 | N-aroylthymidine derivative and agent for lowering toxicity of antitumor active substance |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60174797A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108350018A (en) * | 2015-11-17 | 2018-07-31 | 日产化学工业株式会社 | The manufacturing method of oligonucleotides |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7776838B1 (en) | 1987-10-28 | 2010-08-17 | Wellstat Therapeutics Corporation | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
| DE3856557T2 (en) | 1987-10-28 | 2004-06-03 | Wellstat Therapeutics Corp. | Acyl deoxyribonucleoside derivatives and uses thereof |
| US6329350B1 (en) | 1987-10-28 | 2001-12-11 | Pro-Neuron, Inc. | Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis |
| US5470838A (en) | 1987-10-28 | 1995-11-28 | Pro-Neuron, Inc. | Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine |
| US5736531A (en) | 1987-10-28 | 1998-04-07 | Pro-Neuron, Inc. | Compositions of chemotherapeutic agent or antiviral agent with acylated pyrimidine nucleosides |
| KR930003495B1 (en) * | 1987-10-28 | 1993-05-01 | 프로-뉴우런 인코포레이팃드 | Acyl deoxyribonucleoside derivatives and uses thereof |
| US5968914A (en) | 1987-10-28 | 1999-10-19 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
| DE3883374T2 (en) * | 1987-10-28 | 1993-12-09 | Pro Neuron Inc | ACYLATED URIDINE AND CYTIDINE AND THEIR USE. |
| US6020322A (en) | 1993-11-09 | 2000-02-01 | Pro-Neuron, Inc. | Acyl deoxyribonucleoside derivatives and uses thereof |
| US7173017B1 (en) | 1987-10-28 | 2007-02-06 | Wellstat Therapeutics Corporation | Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis |
| ATE282627T1 (en) * | 1992-12-08 | 2004-12-15 | Wellstat Therapeutics Corp | PYRIMIDINE NUCLEOTIDE PRECURSORS FOR THE TREATMENT OF INFLAMMATORY HEPATITIS |
| WO1994026761A1 (en) * | 1993-05-14 | 1994-11-24 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
| AU1436995A (en) * | 1993-12-30 | 1995-07-17 | Chemgenes Corporation | Synthesis of propargyl modified nucleosides and phosphoramidites and their incorporation into defined sequence oligonucleotides |
| CA2193967C (en) | 1994-07-01 | 2007-09-11 | Reid W. Von Borstel | Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis |
| US6472378B2 (en) | 1998-08-31 | 2002-10-29 | Pro-Neuron, Inc. | Compositions and methods for treatment of mitochondrial diseases |
-
1984
- 1984-02-21 JP JP2951284A patent/JPS60174797A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108350018A (en) * | 2015-11-17 | 2018-07-31 | 日产化学工业株式会社 | The manufacturing method of oligonucleotides |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60174797A (en) | 1985-09-09 |
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